ADP-ribosylation has been coupled to intracellular events associated with smooth muscle cell vasoreactivity, cytoskeletal integrity and free radical damage. Additionally, there is evidence that ADP-ribosylation is required for smooth muscle cell proliferation. Our investigation employed selective inhibitors to establish that mono-ADP-ribosylation and not poly(ADP-ribosyl)ation was necessary for the stimulation of DNA synthesis by mitogens. Mitogen treatment increased concomitantly the activity of both soluble and particulate mono-ADP-ribosyltransferase, as well as the number of modified proteins. Inclusion of meta-iodobenzylguanidine (MIBG), a selective decoy substrate of arginine-dependent mono-ADP-ribosylation, prevented the modification of these proteins. MIBG also blocked the stimulation of DNA and RNA synthesis, prevented smooth muscle cell migration and suppressed the induction of c-fos and c-myc gene expression. An examination of relevant signal transduction pathways showed that MIBG did not interfere with MAP kinase and phosphatidylinositol 3-kinase stimulation; however, it did inhibit phosphorylation of the Rho effector, PRK1/2. This novel observation suggests that mono-ADP-ribosylation participates in a Rhodependent signalling pathway that is required for immediate early gene expression.
Expression of the phosphoenolpyruvate carboxykinase (PEPCK) gene is induced by 3-aminobenzamide, an inhibitor of poly(ADP-ribose) polymerase. Synthesis of PEPCK mRNA is repressed by insulin, but remains detectable in H4IIE hepatoma cells exposed simultaneously to both 3-aminobenzamide and insulin. This capability of 3-aminobenzamide to block the inhibitory actions of insulin suggests that ADPribosylation is required for the regulation of PEPCK gene expression by insulin. Furthermore, neither changes in chromatin condensation nor cell growth status were linked to these events. The inability of 3,4-dihydro-5-methylisoquinolinone (PD128763), a selective inhibitor of poly(ADP-ribose) polymerase, to impede insulin-dependent repression of PEPCK gene expression, however, indicated that 3-aminobenzamide does not operate by inhibiting poly(ADP-ribosyl)ation. The potential involvement of mono(ADP-ribosyl)ation, a process that is also inhibited by 3-aminobenzamide, in the regulation of PEPCK gene activity was then evaluated. Analysis of poly(ADP-ribose) polymerase activity and poly-(ADP-ribosyl)ation confirmed that there were no significant changes in response to insulin, while microsomal mono(ADP-ribosyl)transferase activity was elevated approximately fourfold. An increase in protein hydroxylamine-sensitive mono(ADP-ribosyl)ation was observed following insulin treatment. The sensitivity of the mono(ADP-ribosyl)transferase activity to 3-aminobenzamide but not PD128763 makes it plausible that mono(ADP-ribosyl)ation rather than poly(ADP-ribosyl)ation contributes to the regulation of PEPCK gene expression.Keywords : phosphoenolpyruvate carboxykinase; ADP-ribosylation; 3-aminobenzamide; insulin.Expression of the hepatic phosphoenolpyruvate carboxyki-ments found at position Ϫ1150 and position Ϫ450 [5]. While it has been demonstrated that insulin operates through an insulinnase (PEPCK) gene is transcriptionally regulated by insulin and other humoral agents in response to changes in glucose utiliza-responsive element (IRE) site present at position Ϫ410 [6], neither the proteins that bind to this site nor details of the signalling tion [1, 2]. In the fasting state and under conditions of stress, blood glucose levels are elevated by an increase in PEPCK system that conveys signals from the insulin receptor have been identified. mRNA synthesis through the actions of glucagon and glucocorticoids. In contrast, high blood glucose levels stimulate the reThe repression of PEPCK gene expression by insulin in the lease of insulin, which represses gene activity. Molecular dissec-presence of positive mediators such as glucagon indicates that tion has demonstrated that each humoral agent operates through insulin is a dominant factor [7]. Since glucagon-dependent a distinct regulatory element present in the PEPCK gene pro-CREB phosphorylation is not prevented by insulin, transcripmoter [3]. Glucagon, for instance, functions through the cAMP-tional inactivation likely involves an IRE-binding protein (IRdependent phosphorylation of the cAMP-resp...
Release of angiotensin II in response to vascular injury may promote neointimal hyperplasia, because this hormone can stimulate smooth muscle cell proliferation and migration. This study demonstrates that local application of an angiotensin receptor antagonist, losartan, to the site of injury can effectively prevent neointimal hyperplasia after balloon angioplasty. Application of losartan to the perivascular surface of the injured vessel in a surgical fibrin glue enabled delivery of a dose that exceeds the maximum attainable, via a systemic delivery route. The glue also served as a depot from which the drug was slowly released over time. Treatment with losartan may be a viable approach for controlling neointimal hyperplasia at locations (eg, grafts) that are accessible during a surgical procedure.
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